PROJECT SUMMARY/ABSTRACT Multiple myeloma is an incurable cancer of plasma cells. Myeloma is a mostly incurable form of cancer, with the percent surviving 5 years estimated to be only 50.7% (SEER registry). Myeloma is responsible for more than 12,000 deaths a year in the US, with an estimated 31,000 new cases in 2018, and rates for new myeloma cases have been rising on average 0.9% each year over the last 10 years. Although survival rates have improved over the last 15 years, there is substantial toxicity associated with the chronicity of therapy and most patients will ultimately die of myeloma. Not surprisingly, the financial impact associated with myeloma is significant, particularly costs associated with emerging therapies and with supportive care, are significant. These costs represent a tremendous financial burden to both patients and managed care. Thus, better, faster, less toxic, and affordable myeloma treatments remain a critical need. This project will provide essential new information, required by the FDA, to allow approval of an IND for use of a new drug for treatment of multiple myeloma. The drug is CDDO-2-Pyridyl Imidazolide (?2P-Im? or TTX01), a new triterpenoid synthesized and tested for anti- cancer activities at Dartmouth, and now licensed by Dartmouth to Triterpenoid Therapeutics, Inc. The goal of this Phase 1 grant application will be to determine the in vivo efficacy and pharmacodynamics of 2P-Im in a relevant mouse model of human myeloma. To advance TTX01 toward clinical application, we will define both optimal dose and dosing schedule to provide the most durable clinical response in a well-established, immune competent syngeneic murine model of multiple myeloma (Aim 1). Moreover, we will also provide proof-of-concept data that TTX01 administration can enhance the response to a conventional proteasome inhibitor (such as Ixazomib) currently used for human therapy (Aim 2). Variations in combined dosing regimens will be studied, as will the possibility that TTX01 could suppress the development of important pathology in human myeloma. This includes a detailed study of the potential of TTX01 to prevent osteolytic bone disease in mice; this is a frequent and painful complication of myeloma in patients. Thus, this is a practically targeted application which addresses a significant human health problem. After having completed these in vivo studies with TTX01, we will be able to progress to a more extensive, complete IND-enabling body of work in Phase II, with our long-term goal to commercialize TTX01 as a therapy for multiple myeloma.